1,2,4-Triazoles for treating gout and hyperuricemia

ABSTRACT

The substituted 1,2,4-triazoles of this invention are useful as anti-gout and anti-hyperuricemic agents. Compositions useful in the treatment of gout and hyperuricemia containing a substituted triazole as the active ingredient are also provided.

United States Patent 191 Baldwin et a1.

[451 Feb. 11, 1975 i541 1,2,4-TRIAZOLES FOR TREATING GOUT AND I-IYPERURICEMIA [75] Inventors: John J. Baldwin, Lansdale,

Montgomery County; Frederick C. Novello, Berwyn, Chester County,

both of Pa. [73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: Aug. 29, 1973 [21] App]. No.: 392,841

Related US. Application Data [60] Division of Ser. No. 269,685, July 7, 1972, abandoned, which is a continuation-in-part of Ser. No. 75,785, Sept. 25, 1970, abandoned.

[52] US. Cl 424/263, 424/250, 424/251,

424/258 [51] Int. Cl A61k 27/00 [58] Field of Search 424/263 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,076,136 2/1960 Germany 260/296 OTHER PUBLICATIONS J. Chem. Soc.(C), 1968, pp. 824-830. J. Chem. Soc.(C), 1969, 1056-1060.

Primary Examiner-Frederick E. Waddel] Attorney, Agent, or FirmJerome Behan; Daniel T. Szura 5 7] ABSTRACT 20 Claims, No Drawings 1 1,2,4-TRIAZOLE S FOR TREATING GOUT AND HYPERURICEMIA This is a division of application Ser. No. 269,685, filed July 7, 1972 now abandoned, which in turn was a continuation-in-part of application Ser. No. 75,785 filed Sept. 25, 1970, now abandoned.

FIELD OF THE INVENTION The invention relates to a class of triazoles which are substituted in the 3 and 5 positions and bear optional substituents in the 1 position. The substituent in the 1 position is an alkyl, alkanoyl, carbamoyl or benzyl group. The substituents in the 3 and 5 positions are aryl or heteroaryl groups, or a group derived therefrom.

DESCRIPTION OF THE PRIOR ART The herein-described substituted triazoles have utility as anti-gout and anti-hyperuricemic agents.

Gout is a condition affecting humans and lower aminals, particularly birds and reptiles, which is characterized byperversion of the purine metabolism resulting in an excess of uric acid in the blood, by attacks of acute arthritis, and by formation of chalky deposits in the cartilages of the joints. These deposits are made up chiefly of urates, or uric acid. Hyperuricemia is a condition characterized by an excess of uric acid in the blood.

Uric acid serves no biochemical function in the body and is merely an end product of purine metabolism. It is well known in the art that the purine bases adenine and guanine, which play key roles in a wide variety of chemical processes, both give rise to uric acid in the body. Adenylic acid and guanylic acid are converted to the free purine bases by destructive metabolic enzymes. A portion of the free purine bases is converted to purine ribonucleotides and the remainder is degraded to the free bases xanthine and hypoxanthine. A single enzyme, xanthine oxidase, converts both xanthine and hypoxanthine to uric acid for excretion.

Although human purine biosynthesis can be inhibited at the stage of formyl glycinimide ribotide by the glutamine antagonists azaserine and 6 diazo-5-oxo-lnorleucine, a high incidence of undesirable side effects precludes their being used clinically for this purpose. In recent years, substantial progress has been made in attempting to control the excessive levels of uric acid in patients afflicted with gout through the use of pharmaceutical agents. Uric acid synthesis has been effectively blocked by the use of allopurinol, 4-hydroxypyrazolo- [3,4-d]-pyrimidine, a compound which is a structural isomer of hypoxanthine. Allopurinol acts as a specific.

inhibitor of the enzyme xanthine oxidase, which is responsible for the conversion of both hypoxanthine and xanthine to uric acid. As a direct result of the administration of this compound to patients afflicted with gout, part of the uric acid which would normally end up in the urine is replaced instead by the oxypurines hypoxanthine and xanthine, thus greatly reducing the content of uric acid in serum and urine. Azathioprine has also been employed in patients afflicted by gout to inhibit the excessive purine synthesis, which tends to produce abnormal amounts of uric acid. Other compounds, such as acetylsalicylic acid, thiophenylpyrazolidine, and phenylbutazine have been employed in the treatment of gout. Many of the existing compounds used in the treatment of gout, however, relieve the inflamation and other symptoms connected therewith but have no effect on the conditions which give rise to gouty arthritis or hyperuricemia. Thus, there is still a need for compounds which can be employed in the prophylactic treatment of gout as well as for the treatment of other abnormal conditions associated with hyperuricemia.

The substituted triazoles which are the subject of this invention have been found to be effective anti-gout and anti-hyperuricemic agents in that they will inhibit the action of the enzyme xanthine oxidase and thus reduce the content of uric acid in serum and urine. In addition to their use as anti-gout and anti-hyperuricemic agents, certain of the triazoles exhibit diuretic andhypotensive activity.

SUMMARY OF THE INVENTION DESCRIPTION OF THE PREFERRED EMBODIMENTS The novel 1,2,4-triazoles which are the subject of this invention may be depicted as follows:

R -N R u I i 3 t 5 4 I N2 5 n N1 3 R- 1 5 kl 2 N N l l (I) (la) wherein lower alkyl as, for example, methyl, ethyl or propyl and the like,

amino,

dilower alkylamino wherein the lower alkyl moiety contains from 1-5 carbon atoms as, for example, methyl, ethyl, propyl, butyl or pentyl and the like,

sulfamoyl,

lower alkylsulfamoyl as, for example, me-

thanesulfamoyl or ethanesulfamoyl and the like,

lower alkoxy as, for example, methoxy, ethoxy or propoxy and the like, or

lower alkanoylamino as, for example, mamido, acetamido, propionamido butyramido and the like, and

R is pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl,

pyrimidinyl or pyrazinyl; provided, that when R is pyridyl R is other than pyridyl, phenyl or alkylphenyl.

When the compounds of this invention contain a lower alkyl radical, it is preferred that such radical contain from l-5 carbon atoms such as methyl, ethyl, propyl, butyl or pentyl and the like; lower alkanoyl radicals preferably contain from 2-5 carbons, examples being acetyl, propionyl, butyryl or valeryl and the like.

Also within the scope of the present invention are the alkali metal and alkaline earth metal salts of those triazoles where R, is hydrogen, such as the sodium, potassium, and calcium salts, and the pharmaceutically acceptable quaternary salts such as the methiodides and ethiodides, mineral acid salts such as the hydrochloride or sulfate salts of those compounds wherein the substituent in the 3 and/or 5 position contains at least one basic nitrogen, such as a pyridine ring. Also contemplated by the invention are the N-oxides of a nitrogen heterocycle substituent in the 3 or 5 position.

for-

The following class of products are particularly effective xanthine oxidase inhibitors and, therefore, represent a preferred embodiment of this invention:

wherein R is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, furyl, thienyl, halophenyl, for example, 3-chlorophenyl or 4-chlorophenyl and the like, dihalophenyl, for example, 3,4-dichlorophenyl or 3,5- dichlorophenyl and the like, or haloand dihalosulfamoylphenyl, for example, 3-sulfamoyl-4- chlorophenyl, or 3,4-dichloro--sulfamoylphenyl and the like and R is pyridyl, pyridylmethyl, pyrimidinyl or pyrazinyl, with the proviso that when R is pyridyl R is other than pyridyl. The above products and the nontoxic salts thereof, including the alkali metal and alkaline earth metal salts, are especially effective anti-gout and anti-hyperuricemic agents and, therefore, represent a preferred Subclass of compounds within the scope of this invention.

Those compounds corresponding to Formula lb wherein R is pyridyl, pyrazinyl or pyrimidinyl, and R is halophenyl, dihalo-sulfamoylphenyl, thienyl,.pyrazinyl, furyl, quinolyl, pyrimidinyl or pyridazinyl represent an especially preferred subclass of compounds within the scope of the present invention. Most preferred among the preferred compounds are those wherein R is pyridyl and R is halophenyl.

In addition to their utility as anti-gout and antihyperuricemic agents, the following products are useful as diuretics and hypotensive agents:

N l u NH NH I! II II T \N 1 l wherein R is hydrogen or loweralkyl and R and R are as defined above, and W is loweralkyl wherein the alkyl group contains l-5 carbons. As will be appreciated by those skilled in this art, Compounds 1 and la are the same when R is hydrogen.

As can be seen from the above reaction diagram, a substituted hydrazine compound such as, for example, isonicotinoylhydrazine, is reacted with an imino ester such as, for example ethyl p-chloroiminobenzoate, in a suitable solvent. Either lower boiling solvents. such as methanol or ethanol, or nitromethane, or high boiling solvents, such as decalin, xylene, or dimethylsulfoxide, may be employed. When low boiling solvents are employed, the product of the reaction is usually the intermediate acylamidrazone. A reaction time of 3-20 hours at temperatures of from room temperature to the reflux temperature of the solvent is employed. The intermediate acylamidrazone ll (lll) may be converted to I (la) by heating it in the absence of solvent at temperatures between l25300 C. for from about l5 minutes to one hour or in higher boiling solvents at or near the reflux temperature of the solvent for from about one to twenty hours. The final cyclized product is isolated and purified by techniques known in the art.

When high boiling solvents are employed, the reaction is conveniently carried out at or near the reflux temperature of the solvent. The preferred temperature range is between lOO-200 C. The reaction time is dependent upon the particular temperature range employed. The reaction is carried out without isolation of the intermediate and the final cyclized product is isolated and purified by techniques known in the art. For example, the product may be crystallized from a suitable solvent, such as methanol or ethanol. As can be seen from the above reaction diagram, where R, is loweralkyl, the selection of the particular hydrazine compound and the particular imino ester will depend upon which substituent is desired in the 3 and/or 5 position.

Alternatively, the l,2,4-triazoles of this invention can be prepared by reacting a suitable carbonitrile such as, for example, 4-cyanopyridine, with an alkali metal, such as sodium or potassium in a lower alkanol to form the imino ester. The imino ester is then reacted with a suitable carboxylic acid hydrazide such as, for example, pyrazine carboxylic acid hydrazide, in a suitable solvent, such as methanol or ethanol. The reaction mixture is first heated, preferably at reflux temperatures, for from about one-half to 20 hours, after which the reaction mixture is concentrated by removal of the solvent, and the solid intermediate is heated at elevated temperatures, either in the presence or absence of solvent. When no solvent is employed, a temperature between 100-300 C. for from about minutes to one hour is preferred. The product is collected by techniques known in the art. Where high boiling solvents are employed, the reaction is conveniently carried out at or near the reflux temperature of the solvent. The preferred temperature range is 100-200 C. The reaction time is dependent upon the particular temperature range employed.

Those compounds having a substituent other than hydrogen in the 1 position can also be prepared by reacting a triazole of Formula I where R is hydrogen with an appropriate alkylating or acylating agent. Where R and R are different, a mixture of compounds is obtained, i.e., the substituent R may be substituted on either one of the two adjacent nitrogens. For example, where the substituent is a loweralkanoyl group such as an acetyl or butyryl group, the triazole is reacted with a loweralkyl anhydride such as, for example, acetic anhydride or butyric anhydride. Where the substituent in the 1 position is an alkyl group, alkylation is achieved by reacting the sodium salt of the triazole with an alkylating agent such as, for example, dimethylsulfate. Alkylation of the 1,2,4-triazoles generally occurs in the 1 position. Where the alkyl group is a methyl group, methylation can be achieved by reacting the triazole with diazomethane in a suitable solvent, such as diethylether.

Those compounds wherein the substituent in the 1 position is a carbamoyl or substituted carbamoyl group are prepared by reacting a 3,5-substituted-l ,2,4- triazole with a carbamoyl halide such as, for example, dimethylcarbamoyl chloride in a suitable solvent such as tetrahydrofuran in the presence ofa base, such as, for example, sodium hydride.

An alternate method for preparing those compounds having an alkyl group in the 1 position consists of first reacting a nitrile, such as, for example, 4- cyanopyridine, with an alkali metal, such as sodium, in an alcoholic solvent, such as methanol, at room temperature and adding to this solution a hydrazide, such as, for example, a l-isonicotinoyl-2-loweralkylhydrazine. The reaction is heated, generally at reflux temperature, for about 3-20 hours. Depending upon the nature of the substituent, the final cyclized product is obtained directly or the intermediate acylamidrazone is obtained. In the case where the intermediate is obtained, it may be heated without solvent at about lOO-300 C. for from about 15 minutes to several hours, or the intermediate can be heated in a high boiling solvent such as xylene or decalin at about lOO-200 C. for about 1-20 hours. The alkylated triazole is isolated by techniques known in the art.

Those compounds of this invention which are amine oxides can be prepared by the method described above by employing a nitrile-N-oxide such as, for example, 4-cyanopyridine-N-oxide, as the nitrile reactant, or a hydrazine, such as pyridine-N-oxide-4-carboxylic acid hydrazide.

Representative examples of the compounds within the scope of this invention are:

3-(p-chlorophenyl)-5-( 4-pyridyl )-l ,2,4-triazole, 3-pyrazinyl-5-(4-pyridyl)-l ,2,4-triazole, 3-(3,4-dichlorophenyl)-5-(4-pyridyl)-l,2,4-triazole,

1-ethyl-3,5-di(4-pyrimidyl)-l ,2,4-triazole, 3-(6-quinolyl)-5-(4-pyridyl)-l ,2,4-triazole, 3-(2-furyl)-5-(4-pyridyl)-l ,2,4-triazole, 3-(4-chloro-3-sulfamoylphenyl)-5-(4-pyridyl)-l ,2,4-

triazole,

3-( 3,S-dimethoxyphenyl)-5-(4-pyridyl)-l ,2,4-

triazole,

3-(m-chlorophenyl)-5 -(4-pyridyl)-l ,2,4-triazole,

3-(p-bromophenyl )-5-(4-pyridyl)-l ,2,4-triazole,

3-( 2-naphthyl )-5-(4-pyridy] )-l ,2,4-triazole,

3-( 3 ,4-dichloro-S-sulfamoylphenyl )-5-( 4-pyridyl 1,2,4-triazole,

3,5-di(4-pyrimidyl )-l ,2,4-triazole,

N-methyl-4-[3-(p-chlorophenyl)-l ,2,4-triazolyl-51- pyridiniumiodide,

N-methyl-4-[3-(m-chlorophenyl)-l ,2,4-triazolyl-5 1 pyridiniumiodide,

3-(p-chlor'ophenyl)-5-(4-pyridazinyl )-1 ,2,4-triazole,

l-butyryl-3-(p-chlorophenyl)-5-(4-pyridyl)-l ,2,4-

triazole,

l-acetyl-3-( 3,4-dichlorophenyl)-5-( 4-pyridyl)-l ,2,4

triazole,

l-methyl-3-(3 ,S-dimethoxyphenyl )-5-(4-pyridyl 1,2,4-triazole,

l-benzyl-3 ,5-di(4-pyrimidyl)-1,2,4-triazole,

3-(3,5-dimethoxyphenyl)-5-(2-pyrazinyl)-l ,2,4-

triazole,

3-(p-methoxyphenyl )-5-( 3-pyridyl)-l ,2,4-triazole,

3 -(p-sulfamoylphenyl)-5-pyrazinyl-l ,2,4-triazole,

l-methyl-3-(4-pyridyl)-5-(p-chlorophenyl)-l ,2,4-

triazole,

l-acetyl-3-( 6-quinolyl )-5-(p-dimethylaminophenyl 1,2,4-triazole,

and

l-'methyl-3,-(p-Chlorophenyl)-5-(4-pyridyl )-l ,2,4

triazole.

The substituted triazoles which are the subject of this invention inhibit the action of the enzyme xanthine oxidase resulting in a significant decrease in the concentration of uric acid in the blood and urine and are, therefore, capable of aborting attacks of gout.

For testing purposes, xanthine oxidase obtained from milk may be employed to demonstrate the ability of the substituted triazoles to inhibit the enzyme. The general procedure is to employ a 5-10 unit suspension of the enzyme per milliliter of 60% saturated ammonium sulfate of the enzyme; 1 unit of such a suspension converts 1 umole of xanthine to uric acid per minute. Generally, for a 1-day assay, about 0.05 ml. of enzyme is diluted with about 3 ml. of buffer. As the buffer, tris buffer (0.05 mole, pH 7.4) may be employed. The inhibitor to be treated is dissolved in'buffer or a suitable solvent, such as dimethylsulfoxide; the same solvent is used to dilute the solution. The buffer, hypoxanthine and solvent are placed in a cell, and the enzyme solution is then added, and the rate of increase in absorbance at 290mg. is noted with a recording spectrophotometer. Generally, sufficient enzyme is employed to give about 0.1 absorbance units change per minute, and sufficient inhibitor is used to give 30-70% inhibition. The ,LLM concentration of inhibitor necessary for 50% inhibition (V /V, 32 2) is determined by plotting V /V, against I, where V velocity without inhibitor, V, velocity with inhibitor, and l inhibitor concentration.

The therapeutically active substituted triazoles can be administered as the active ingredient in association with a pharmaceutically acceptable carrier in the form of tablets, elixirs, capsules, and the like. These preparations may be made by any of the known pharmaceutical methods. For example, in tablet form, they are compounded with an inert pharmaceutical carrier which may contain a suitable binder such as, for example, guns, starches, and sugars. They may also be incorporated into a gelatin capsule or formulated into elixirs which have the advantage of being susceptible to manipulations in flavor by the addition of standard natural or synthetic flavoring materials. The compound is generally administered in compositions which are so proportioned as to afford a unit dosage of about 30 mg. to 1.5 gm. per day. The preferred dosage level, however, is about 100-800 mg. per day.

The following examples serve to illustrate typical tablet, capsule, and elixir formulations incorporating the therapeutically active substituted triazoles of this invention:

FORMULATION I COMPRESSED TABLET COMPRISING 0.5 GM. OF ACTIVE INGREDIENT INGREDIENT AMOUNT MG.

3-(p-chlorophenyl )-5-(4pyridyl)- 1.2 ,4-triazole 500.0 Starch paste 12%72, 100 cc. allow. 1 4i D Starch, U.S.P. Corn 25.0 Magnesium stearate LS The 3-(p-chlorophenyl)-5-(4-pyridyl)-l,2,4-triazole is granulated with the starch paste and while moist passed through a No. 14 screen, dried at 45 C. for 20 hours, and then passed 3 times through a No. 14 screen. The starch is then passed through a No. 90 bolting cloth onto the granulation, and all ingredients are blended thoroughly. The magnesium stearate is passed through a No. bolting cloth onto the granulation, and these ingredients are blended, after which the granulation is compressed into tablets using a fourteen thirty-seconds inch flat, bevelled, scored punch having a thickness of 0.205 t 0.005 inch yielding 1,000 tablets each weighing 0.543 grams.

FORMULATION IX: ENCAPSULATION FOR 250 MG CAPSULE INGREDIENT AMOUNT MG.

3-pyrazinyl-5-(4-pyridyl)-1,2,4- triazole 250 Lactose 93 Talc 7 Blend lactose, talc and the 3-pyrazinyl-5-(4-pyridyl)- 1,2,4-triazole in suitable blending equipment, and encapsulate into a No. 2 capsule at a target weight of 350 mg.

FORMULATION III: LIQUID SUSPENSION FORMULA INGREDIENT AMOUNT q./l.

Veegum I-I.V. 3.0 Water 150.0 Methyl paraben 1.0 1-rnethyl-5-(4-pyridy1)-3-(p-chloropheny1)-1 ,2,4-triazole 50.0 Kaolin 10.0 Flavor 1.0

Glycerin. 9.5 to 1 liter Suspend Veegum in water with vigorous agitation, add methyl paraben and allow to stand overnight to ensure complete hydration of Veegum. In separate vessel suspend l-methyl-5-(4-pyridyl)-3-(p-chlorophenyl)-1,2,4- triazole in about 750 cc. of glycerin. Add kaolin and stir until homogeneous. Slowly add aqueous dispersion of Veegum and methyl paraben. Add flavor and continue agitation for 1 hour to ensure homogeneity. 0.8. with remaining glycerin to 1:1. Stir until homogeneous. 1 Teaspoonful contains 250 mg. of l-methyl-5-(4- pyridyl )-3 -(p-chlorphenyl)-1,2,4-triazole.

The following examples are given for purposes of i1- lustration and not by way of limitation:

EXAMPLE 1 EXAMPLES 2 22 The following compounds are prepared by the reaction procedure described in Example 1:

EXAMPLE HYDRAZIDE NlTRlLE COMPOUND MELTING POINT 2 3,4-dichlorobenzoyl- 4-cyanopyridine 5-(4-pyridyl)-3-(3,4-dichloro- 345-346.5C.

hydrazine phe nyl )-l ,2,4-triazole 3 6-quinolinecarboxylic 4cyanopyridine 5-(4-pyridyl)3-(6-quinolyl)- 313-314,5C

acid hydrazide 1,2,4-triazole 4 3-pyridyl acetic acid 4-cyanopyridine 3-(3-picolyl)-5-(4-pyridyl)- l6l-l62C.

hydrazide 1,2,4-triazole 5 2-furoic acid hydrazide 4-cyanopyridine 5-(4-pyridyl)-3-(2-furyl)- 2162l7C.

1,2,4-triazole 6 4-chloro-3-sulfamoyl- 4-cyanopyridine 5-(4-pyridyl)-3-(4chloro-3- 335.5-336.5C.

benzoyl h drazine sulfamoyl henyl)-l,2,4-triazole 7 3,5-dimet oxy- 4-cyanopyridine 5(4-pyri yl)-3-(3,5-dimethoxy- 252253.5C.

benzoylhydrazine phenyl l ,2,4-triazole 8 m-chlorobenzoyl- 4-cyanopyridine 5-( 4-pyridyl )-3-( m-chlorophenyl 269-271 C.

hydrazine 1,2,4-triazole 9 pyrazinecarboxylic Z-cyanopyridine 5-( Z-pyridyl )-3-pyrazinyll ,2,4- 248-250C.

acid hydrazide triazole l isonicotinic acid Z-cyanopyrimidine -(4pyridyl)-3-(2-pyrimidinyl)- 274276C.

hydrazide 1,2,4-triazole l l 3,5-dichlorobenzoyl- 4-cyanopyridine 5-(4-pyridyl)-3-( 3,5-dichloro- 298299.5C.

hydrazine phe nyl l ,2,4-triazole l2 p-bromobenzoyl- 4 cyanopyridine 5-(4-pyridyl)-3-(p-bromophenyl)- 263264C.

hydrazine l ,2,4-triazole l3 4-pyridazinecarboxylic 4-cyan0p yridine 5-(4-pyridyl )-3-( 4pyridazinyl 276-278C.

acid hydrazide l,2,4-triazole l4 p-methoxybenzoyl 4-cyanopyridine 5-( 4-pyridyl )-3-( p-methoxy- 247249C.

hydrazine phe nyl l ,2,4-triazole l5 2-thiophenecarboxylic 4-cyanop yridine 5-(4pyridyl )-3-( 2-thie nyl 24024 l .5C.

acid hydrazide 1,2,4-triazole 16 p-sulfamoylbenzoyl- 4-cyanop yridine 5-( 4-pyridyl )-3-(p-sulfamoyl 301-302C.

hydrazine phenyl )-l ,2,4-triazole l7 Z-naphthoic acid 4-cyanopyridine 5-(4-pyridyl)-3-(2-naphthyl)- 289-390C.

hydrazide 1,2,4-triazole l8 3,4-dichloro-5- 4-cyanop yridine 5-(4-pyridyl )-3-( 3 ,4-dichloro- 3 30C.(dec.)

sulfamoylbenzoyl- 5-sulfamoylphenyl)-1,2,4- hydrazine triazole 19 2-pyridylacetic 4-cyanopyridine 5-( 4-pyridyl )-3-( 2-picolyl)- l90l9 1C.

acid hydrazide l,2,4-triazole 20 isonicotinic acid 4-cyanopyrirnidine 5-(4-pyridyl)-3-(4-pyrimidinyl)- 285286.5C.

hydrazide l ,2,4-triazole 2l 4-pyrimidinecarboxylic 4-cyanopyrimidine 3,5-di(4-pyrimidinyl)-1,2,4- 302-304C.

acid hydrazide triazole 22 2,4-dichloro-5- 4-cyanopyridine 5-(4-pyridyl)-3-(2.4-dichloro- 297299C.

sulfamoylbenzoyl- S-sulfarnoylphenyl l 2,4- hydrazine triazole EXAMPLE 23 4-[ 3-(m-chlorophenyl)- 1 ,2,4-triazolyl-5 ]-pyridmium 3-(p-Chlorophenyl)-5-(4-Pyridyl)-1,2,4-Triazole To a suspension of isonicotinoylhydrazine (10.9 grams, 0.03 mole) in methanol (250 ml.) is added a solution of ethyl p-chloroiminobenzoate (14 grams, 0.08 mole) in methanol (50 ml.). The reaction mixture is refluxed for minutes and is then concentrated until a solid separates out of solution. The mixture is then cooled, and the intermediate acylamidrazone is collected by filtration. The acyclic intermediate is then heated at 280 C. for 15 minutes, after which it is cooled to room temperature, Upon recrystallization from ethanol-water and sublimation, 3-(pchlorophenyl)-5-(4-pyridyl)-l,2,4-triazole is obtained, m.p. 264.5265.5 C.

EXAMPLE 24 When in the above procedure 3-(m-chlorophenyl)-5- (4-pyridyl)-l,2,4-triazole is employed in place of 3-(pchlorophenyl)-5-(4-pyridy])-l,2,4-triazole, N-methyliodide is obtained, m.p. 280-281 C.

EXAMPLE 25 3 ,S-Dipyrazinyl- 1 ,2,4-Triazole Sodium (50 mg.) is added to 2-cyanopyrazine (1 gram, 0.01 mole) in 20 ml. of methanol. The solution is allowed to stand 1 hour at room temperature and is added to a suspension of pyrazine carboxylic acid hydrazide (1.4 grams, 0.01 mole) in.50 ml. of methanol. The reaction mixture is heated at reflux for 2 hours and then at room temperature for 16 hours. After cooling, the intermediate acylamidrazone is removed by filtration and is then heated at temperatures between 200 to 260 C. over 2 /2 hours. After cooling and recrystallization from methanol-water, 0.8 grams of 3,5- dipyrazinyl-l,2,4-triazole, m.p. 269-270.5 C. is obtained.

EXAMPLE 26 l-Acetyl-3 ,S-Dipyrazinyl-l ,2,4-Triazole A suspension of 3,5-dipyrazinyl-1,2,4-triazole (0.5 grams) in 20 ml. of acetic anhydride is heated on a steam bath for 17 hours. The resulting solution is filtered and concentrated to a solid. After recrystallization from benzene-hexane, 250 mg. of l-acetyl-3,5- dipyrazinyl-l,2,4-triazole is obtained, m.p. l28-l30 C.

EXAMPLE 27 l-Dimethylcarbamoyl-3 ,S-Dipyrazinyll ,2,4-Triazole To 2.25 g. (0.01 mole) of 3,5-dipyrazinyl-l,2,4- triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride (.42 g., 0.01 mole). The reaction mixture is heated at reflux for 1 hour, cooled, and a solution of dimethylcarbamoyl chloride (1 gram, 0.01 mole) in ml. of tetrahydrofuran is added dropwise. The reaction mixture is then refluxed 4 hours, cooled, filtered and concentrated to a solid. After recrystallization from benzene l-dimethylcarbamoyl-3,5-dipyrazinyl-l ,2,4- triazole is obtained.

EXAMPLE 28 3-(p-Aminophenyl)-5-(4-Pyridyl l ,2,4-Triazole To 4-cyanopyridine (4.2 g.) in methanol (60 ml.) is added sodium (0.2 g.). The solution is allowed to stand for 0.5 hour at room temperature and is then added to a suspension of p-aminobenzhydrazide (6.4 g.) in 150 ml. of methanol. The resulting solution is heated 20 hours at reflux during which time a solid separates. The solid is filtered and heated to 245 C. over 1 hour and maintained at that temperature for an additional minutes. After cooling the solid is recrystallized from a mixture of acetonitrile and water to yield 3-(paminophenyl)-5-(4-pyridyl)-l,2,4-triazole (2 g.) m.p. 25l-252.5 C.

Analysis calculated for C l'l N Calculated: 5 C,65 .95; H4? .6

2 Found: 1

Upon substituting p-(dimethylamino)benzoylhydrazine and 3-cinnolylcarbohydrazine for paminobenzhydrazide in the above method and otherwise following the procedure described therein, there is thus obtained 3-(p-dimethylaminophenyl)-5-(4- pyridyl )-l ,2,4-triazole and 3-( 3-cinnolyl)-5-(4- pyridyl)-l ,2,4-triazole.

EXAMPLE 29 3-(p-Acetylaminophenyl)-5-(4-Pyridyl)-1,2,4-Triazole To 3-(p-aminophenyl)-5-(4-pyridyl)-l ,2,4-triazole (l g.) is added acetic anhydride ml.) and the resulting suspension is heated 18 hours on a steam bath. The excess acetic anhydride is removed under reduced pressure and water ml.) is added to the'residue. After stirring 0.5 hour, the solid is filtered and recrystallized to yield 3-(p-acetylaminophenyl)-5-4-pyridyl)- 1,2 ,4-triazole.

EXAMPLE 30 chlorophenyl)-5-(4-pyridyl)-l,2,4-triazole m.p. 191

C. is obtained.

Analysis calculated for C H CINQ Calculated: N,20.70; C,62.l l; H,4.10 Found: N,20.66; C,62.07; H406 Analysis calculated for C H CIN Calculated: N,20.70;C,62.l1; H4. 10 Found: N.20.6l; C,62.l2; H,4.l0

15 EXAMPLE 31 l-Methyl-3-(4-Pyrimidinyl)-5-(4-Pyridyl)-1,2,4- Triazole and l-Methyl-3-(4-Pyridyl)-5-(4- Pyrimidinyl)-1,2,4-Triazole To 3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole (2.2. g.) in dry tetrahydrofuran (125 ml.) is added 57% sodium hydride in mineral oil (0.46 g.). After refluxing 0.5 hour, methyliodide (1.4 g.) is added and the mixture is heated an additional three hours at reflux. The reaction mixture is cooled, filtered and concentrated to a solid. The solid is triturated with water and filtered to yield a mixture of 1-methyl-3-(4-pyrimidinyl)-5-(4- pyridyl)-l ,2,4-triazole, and l-methyl-3-(4-pyridyl)-5- l-pyrimidinyl)-1,2,4-triazole.

EXAMPLE 32 l-Benzyl-3 ,5-bis(4-Pyrimidinyl l ,2,4-Triazole To 3,5-bis(4-pyrimidinyl)-l ,2,4-triazole (4.5 g.) in dry tetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (0.93 g.). The mixture is heated at reflux for minutes, cooled and concentrated to a solid which is then dissolved in N,N-dimethylformamide (70 ml.). Benzylchloride (2.8 g.) is added and the solution is heated for four hours on a steam bath. The 0 reaction mixture is concentrated to a gum, water is added and the resulting solid is removed by filtration. After recrystallization substantially pure l-benzyl-3,5- bis(4-pyrimidinyl)-1,2,4-triazole is obtained.

EXAMPLE 33 l-Methyl-3,5-bis(4-Pyrinidinyl)-1,2,4-Triazole To 3,5-bis(4-pyrimidinyl)-l,2,4-triazole (2.3 g.) in dry tetrahydrofuran 125 ml.) is added 57% sodium hydride in mineral oil (0.46 g.). After refluxing 0.5 hour, methyl iodide (1.4 g). is added and the mixture is heated at reflux an additional three hours. The reaction mixture is cooled, filtered and concentrated to a solid which after recrystallization yields substantially pure l-methyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole.

EXAMPLE 34 l-Carbamoyl-3-(4-Pyrimidinyl)-5-(4-Pyridyl)- 1,2,4Triazole and l-Carbamoyl-3-(4-Pyridyl)-5-(4- pyrimidinyl)-1,2,4-Triazole To 3-(4-pyrimidinyl)-5-(4-pyridyl)-1,2,4-triazole (4.5 g.) in dry tetrahydrofuran (20 ml.) is added 57% sodium hydride in mineral oil (0.93 g.). The mixture is heated at reflux for 0.5 hour, cooled and a saturated solution of phosgene in tetrahydrofuran ml.) is added dropwise with stirring at room temperature. After 1 hour the solution is concentrated to one-half volume and added dropwise to a saturated solution of ammonia in ethanol 100 ml. After one hour the mixture is cont z l h in tbs s miil R R N 3 or 3 N\N/CR R -N cR or a non-toxic pharmaceutically acceptable salt thereof wherein R, is hydrogen or C alkyl;

R, is monoor di-substituted phenyl wherein the substituents are chloro, bromo, amino, or acetylamino; and

R is pyridyl.

2. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is monoor di-chlorophenyl.

3. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is monochlorophenyl.

4. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is monochlorophenyl and R is hydrogen.

5. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is monochlorophenyl, R is hydrogen and R is 4-pyridyl.

6. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is 3- chlorophenyl, R is hydrogen and R is 4-pyridyl.

7. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is 4- chlorophenyl, R, is hydrogen and R is 4-pyridyl.

8. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is dichlorophenyl and R, is hydrogen.

9. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is 3,4- dichlorophenyl, R, is hydrogen and R is 4-pyridyl.

10. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R is 3,5- dichlorophenyl, R, is hydrogen and R is 4-pyridyl.

11. A method for decreasing an elevated concentration of uric acid in the blood and urine of humans and lower animals by the administration in a pharmaceutically acceptable dosage form an anti-gout and anti-uric acid effective amount of an agent having the formula or a non-toxic pharmaceutically acceptable salt thereof wherein R is hydrogen or C alkyl;

R is monoor di-substituted phenyl wherein the substituents are chloro, bromo, amino, or acetylamino; and

R is pyridyl.

12. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is monoor di-chlorophenyl.

13. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is mono-chlorophenyl.

14. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is mono-chlorophenyl, and R is. hydrogen.

15. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is mono-chlorophenyl, R is hydrogen and R is 4-pyridyl.

16. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is 3-chlorophenyl, R is hydrogen and R is 4-pyridyl.

17. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is 4'chlorophenyl, R, is hydrogen and R is 4-pyridyl.

18. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is di-chlorophenyl and R is hydrogen.

19. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is 3,4-dichlorophenyl R is hydrogen and R is 4-pyridyl.

20. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R is 3,5-dichlorophenyl, R is hydrogen and R is 4-pyridyl. 

1. A PHARMACEUTICAL PREPARATION HAVING XANTHINE OXIDASE INHIBITING ACTIVITY USEFUL FOR TREATING GOUT AND HYPERURICEMIA IS DOSAGE UNIT FROM COMPRISING A PHARMACEUTICALLY ACCEPTABLE CARRIER AND AS THE XANTHINE OXIDASE INHIBITING AGENT FROM ABOUT 30 MG. TO 1.5 G. OF A THIADIAZOLE HAVING THE FORMULA
 2. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is mono- or di-chlorophenyl.
 3. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is mono-chlorophenyl.
 4. A pharmaceutical preparation of claim 1 wherein in the xanthiNe oxidase inhibiting agent R3 is mono-chlorophenyl and R1 is hydrogen.
 5. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is mono-chlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 6. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is 3-chlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 7. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is 4-chlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 8. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is dichlorophenyl and R1 is hydrogen.
 9. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is 3,4-dichlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 10. A pharmaceutical preparation of claim 1 wherein in the xanthine oxidase inhibiting agent R3 is 3,5-dichlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 11. A method for decreasing an elevated concentration of uric acid in the blood and urine of humans and lower aminals by the administration in a pharmaceutically acceptable dosage form an anti-gout and anti-uric acid effective amount of an agent having the formula
 12. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is mono- or di-chlorophenyl.
 13. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is mono-chlorophenyl.
 14. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is mono-chlorophenyl, and R1 is hydrogen.
 15. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is mono-chlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 16. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is 3-chlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 17. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is 4-chlorophenyl, R1 is hydrogen and R5 is 4-pyridyl.
 18. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is di-chlorophenyl and R1 is hydrogen.
 19. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is 3,4-dichlorophenyl R1 is hydrogen and R5 is 4-pyridyl.
 20. A method of claim 11 wherein in the xanthine oxidase inhibiting agent R3 is 3,5-dichlorophenyl, R1 is hydrogen and R5 is 4-pyridyl. 